Anti-pd-l1 antibodies

Abstract

The present invention relates to antigen binding molecules, particularly antibodies, fragments and variants thereof, that bind to the programmed death-ligand 1 (PD-L1) in a pH-dependant manner, competing with PD-L1 binding to the inhibitory receptor programmed death 1 polypeptide (PD-1) and co-stimulatory molecule CD80, and the use of said antigen binding molecules in treating and/or preventing diseases such as cancer.

1 . An anti-PD-L1 antigen binding molecule comprising:
 a VLCDR1 comprising an amino acid sequence of any one of SEO ID NOs 16, 12, 10, 14, 18, or 2; or   a VLCDR1 having at least 80% identity to an amino acid sequence of any one of SEQ ID NOs 16, 12, 10, 14, 18, or 2.   
     
     
         2 . (canceled) 
     
     
         3 . The anti-PD-L1 antigen binding molecule of  claim 1  comprising:
 a VHCDR1 having at least 80% identity to amino acid sequence of SEQ ID NO 6; 
 a VHCDR2 having at least 80% identity to amino acid sequence of SEQ ID NO 7; 
 and a VHCDR3 having at least 80% identity to amino acid sequence of SEQ ID NO 8; 
 and/or 
 a VLCDR2 having at least 80% identity to amino acid sequence of SEQ ID NO 3; 
 and a VLCDR3 having at least 80% identity to amino acid sequence of SEQ ID NO 4. 
 
     
     
         4 . The anti-PD-L1 antigen binding molecule of  claim 1  comprising:
 a VHCDR1 comprising the amino acid sequence of SEQ ID NO 6; 
 a VHCDR2 comprising the amino acid sequence of SEQ ID NO 7; 
 and a VHCDR3 comprising the amino acid sequence of SEQ ID NO 8; 
 and/or 
 a VLCDR1 comprising the amino acid sequence of any one of SEQ ID NOs; 16, 12, 10, 14, 18, or 2; 
 a VLCDR2 comprising the amino acid sequence of SEQ ID NO 3; and 
 a VLCDR3 comprising the amino acid sequence of SEQ ID NO 4. 
 
     
     
         5 . The anti-PD-L1 antigen binding molecule of  claim 1  comprising:
 a heavy chain variable region having at least 80% identity to amino acid sequence SEQ ID NO: 5; and/or 
 a light chain variable region having at least 80% identity to an amino acid sequence selected from the group consisting of SEQ ID NO: 15, SEQ ID NO: 11, SEQ ID NO: 9, SEQ ID NO: 13, SEQ ID NO: 17 and SEQ ID NO: 1. 
 
     
     
         6 . The anti-PD-L1 antigen binding molecule of  claim 1  comprising:
 a heavy chain variable region comprising amino acid sequence SEQ ID NO: 5; 
 and/or 
 a light chain variable region comprising the amino acid sequence selected from the group consisting of SEQ ID NO: 15, SEQ ID NO: 11, SEQ ID NO: 9, SEQ ID NO: 13, SEQ ID NO: 17 and SEQ ID NO: 1. 
 
     
     
         7 . The anti-PD-L1 antigen binding molecule of  claim 1 , wherein the antigen binding molecule is selected from the group consisting of:
 (a) an anti-PD-L1 antigen binding molecule comprising a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYGMY (SEQ ID NO: 6), a VHCDR2 comprising the amino acid sequence VISYDGSNKYYADSVKG (SEQ ID NO: 7), a VHCDR3 comprising the amino acid sequence GALTHWGVVIGDGMDV (SEQ ID NO: 8); and   a light chain variable region comprising a VLCDR1 comprising the amino acid sequence RETELSRRLHYVR (SEQ ID NO: 16), a VLCDR2 comprising the amino acid sequence EDDQRPS (SEQ ID NO: 3) and a VLCDR3 comprising the amino acid sequence QNVLTTPWT (SEQ ID NO: 4);   or comprising VHCDR and VLCDR sequences that are at least 90%, at least 95%, at least 98% or at least 99% identical thereof;   (b) an anti-PD-L1 antigen binding molecule comprising a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYGMY (SEQ ID NO: 6), a VHCDR2 comprising the amino acid sequence VISYDGSNKYYADSVKG (SEQ ID NO: 7), a VHCDR3 comprising the amino acid sequence GALTHWGVVIGDGMDV (SEQ ID NO: 8); and   a light chain variable region comprising a VLCDR1 comprising the amino acid sequence VLSPRTHAGHYYR (SEQ ID NO: 12), a VLCDR2 comprising the amino acid sequence EDDQRPS (SEQ ID NO: 3) and a VLCDR3 comprising the amino acid sequence QNVLTTPWT (SEQ ID NO: 4);   or comprising VHCDR and VLCDR sequences that are at least 90%, at least 95%, at least 98% or at least 99% identical thereof;   (c) an anti-PD-L1 antigen binding molecule comprising a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYGMY (SEQ ID NO: 6), a VHCDR2 comprising the amino acid sequence VISYDGSNKYYADSVKG (SEQ ID NO: 7), a VHCDR3 comprising the amino acid sequence GALTHWGVVIGDGMDV (SEQ ID NO: 8); and   a light chain variable region comprising a VLCDR1 comprising the amino acid sequence ISNDVPASGHYHR (SEQ ID NO: 10), a VLCDR2 comprising the amino acid sequence EDDQRPS (SEQ ID NO: 3) and a VLCDR3 comprising the amino acid sequence QNVLTTPWT (SEQ ID NO: 4);   or comprising VHCDR and VLCDR sequences that are at least 90%, at least 95%, at least 98% or at least 99% identical thereof;   (d) an anti-PD-L1 antigen binding molecule comprising a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYGMY (SEQ ID NO: 6), a VHCDR2 comprising the amino acid sequence VISYDGSNKYYADSVKG (SEQ ID NO: 7), a VHCDR3 comprising the amino acid sequence GALTHWGVVIGDGMDV (SEQ ID NO: 8); and   a light chain variable region comprising a VLCDR1 comprising the amino acid sequence MRTGTGNKGHYTR (SEQ ID NO: 14), a VLCDR2 comprising the amino acid sequence EDDQRPS (SEQ ID NO: 3) and a VLCDR3 comprising the amino acid sequence QNVLTTPWT (SEQ ID NO: 4);   or comprising VHCDR and VLCDR sequences that are at least 90%, at least 95%, at least 98% or at least 99% identical thereof;   (e) an anti-PD-L1 antigen binding molecule comprising a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYGMY (SEQ ID NO: 6), a VHCDR2 comprising the amino acid sequence VISYDGSNKYYADSVKG (SEQ ID NO: 7), a VHCDR3 comprising the amino acid sequence GALTHWGVVIGDGMDV (SEQ ID NO: 8); and   a light chain variable region comprising a VLCDR1 comprising the amino acid sequence RGTGSSFHHKYVR (SEQ ID NO: 18), a VLCDR2 comprising the amino acid sequence EDDQRPS (SEQ ID NO: 3) and a VLCDR3 comprising the amino acid sequence QNVLTTPWT (SEQ ID NO: 4);   or comprising VHCDR and VLCDR sequences that are at least 90%, at least 95%, at least 98% or at least 99% identical thereof; and   (f) an anti-PD-L1 antigen binding molecule comprising a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYGMY (SEQ ID NO: 6), a VHCDR2 comprising the amino acid sequence VISYDGSNKYYADSVKG (SEQ ID NO: 7), a VHCDR3 comprising the amino acid sequence GALTHWGVVIGDGMDV (SEQ ID NO: 8); and   a light chain variable region comprising a VLCDR1 comprising the amino acid sequence TRSSGSIASNYVQ (SEQ ID NO: 2), a VLCDR2 comprising the amino acid sequence EDDQRPS (SEQ ID NO: 3) and a VLCDR3 comprising the amino acid sequence QNVLTTPWT (SEQ ID NO: 4);   or comprising VHCDR and VLCDR sequences that are at least 90%, at least 95%, at least 98% or at least 99% identical thereof.   
     
     
         8 . The anti-PD-L1 antigen binding molecule of  claim 1 , wherein the antigen-binding molecule comprises a heavy chain variable region and a light chain variable region selected from the group consisting of:
 (a) a VH comprising the amino acid sequence of SEQ ID NO: 5 and a VL comprising the amino acid sequence of SEQ ID NO: 15 or comprising VH and VL sequences that are at least 90%, at least 95%, at least 98% or at least 99% identical to SEQ ID NO: 5 and SEQ ID NO: 15, respectively;   (b) a VH comprising the amino acid sequence of SEQ ID NO: 5 and a VL comprising the amino acid sequence of SEQ ID NO: 11 or comprising VH and VL sequences that are at least 90%, at least 95%, at least 98% or at least 99% identical to SEQ ID NO: 5 and SEQ ID NO: 11, respectively;   (c) a VH comprising the amino acid sequence of SEQ ID NO: 5 and a VL comprising the amino acid sequence of SEQ ID NO: 9 or comprising VH and VL sequences that are at least 90%, at least 95%, at least 98% or at least 99% identical to SEQ ID NO: 5 and SEQ ID NO: 9, respectively;   (d) a VH comprising the amino acid sequence of SEQ ID NO: 5 and a VL comprising the amino acid sequence of SEQ ID NO: 13 or comprising VH and VL sequences that are at least 90%, at least 95%, at least 98% or at least 99% identical to SEQ ID NO: 5 and SEQ ID NO: 13, respectively;   (e) a VH comprising the amino acid sequence of SEQ ID NO: 5 and a VL comprising the amino acid sequence of SEQ ID NO: 17 or comprising VH and VL sequences that are at least 90%, at least 95%, at least 98% or at least 99% identical to SEQ ID NO: 5 and SEQ ID NO: 17, respectively; and   (f) a VH comprising the amino acid sequence of SEQ ID NO: 5 and a VL comprising the amino acid sequence of SEQ ID NO: 1 or comprising VH and VL sequences that are at least 90%, at least 95%, at least 98% or at least 99% identical to SEQ ID NO: 5 and SEQ ID NO: 1, respectively.   
     
     
         9 . The anti-PD-L1 antigen binding molecule of  claim 1  wherein the anti-PD-L1 antigen binding molecule is an antibody selected from the group consisting of 8B06, 8D06, 8G08, 8A04, 8D04, and 2A09. 
     
     
         10 .- 12 . (canceled) 
     
     
         13 . The anti-PD-L1 antigen binding molecule of  claim 1  wherein the anti-PD-L1 antigen binding molecule is an antibody or antigen binding fragment or derivative thereof, optionally wherein the antibody, antigen binding fragment or derivative is a Fab, F(ab′)2, Fv, scFv, dAb, Fd, or a diabody. 
     
     
         14 .- 15 . (canceled) 
     
     
         16 . The anti-PD-L1 antigen binding molecule of  claim 13 , wherein the antibody or antigen binding fragment or derivative thereof is an IgA, IgD, IgE, IgG, IgM or IgY antibody or antigen binding fragment or derivative thereof. 
     
     
         17 . The anti-PD-L1 antigen binding molecule of  claim 16 , wherein the antibody or antigen binding fragment or derivative thereof is bispecific. 
     
     
         18 . The anti-PD-L1 antigen binding molecule of  claim 1 , wherein the anti-PD-L1 antigen binding molecule specifically binds to PD-L1 in a pH-dependent manner. 
     
     
         19 . The anti-PD-L1 antigen binding molecule of  claim 1 , wherein the anti-PD-L1 antigen binding molecule has a higher affinity for PD-L1 at pH 6.0 than at pH 7.4. 
     
     
         20 .- 22 . (canceled) 
     
     
         23 . The anti-PD-L1 antigen binding molecule of  claim 1 , wherein the anti-PD-L1 antigen binding molecule
 a. reverses immune suppression; and/or   b. enhances T cell immunity when administered in vivo or in vitro.   
     
     
         24 . A pharmaceutical composition comprising the anti-PD-L1 antigen binding molecule of  claim 1  and a pharmaceutically acceptable excipient. 
     
     
         25 . The pharmaceutical composition of  claim 24 , further comprising an additional therapeutically active agent. 
     
     
         26 .- 28 . (canceled) 
     
     
         29 . The pharmaceutical composition of  claim 24 , wherein the pharmaceutical composition is administered to a patient in combination with at least one of another therapy and an additional therapeutically active agent. 
     
     
         30 . A method of treating cancer in a subject in need thereof comprising:
 administering the anti-PD-L1 antigen binding molecule according to  claim 1 ; or administering a pharmaceutical composition comprising the anti-PD-L1 antigen binding molecule according to  claim 1 .   
     
     
         31 . The method of  claim 30 , wherein the cancer is selected from the group consisting of melanoma, metastatic cancer, non-small cell lung cancer, head and neck cancer, Hodgkin's lymphoma, urothelial carcinoma, gastric cancer, cervical cancer, hepatocellular carcinoma and bladder cancer.